Anabolically active 2-chlor-delta1-androsten-17-ol-3-ones and method of making same



Patented Dec. 38, 1962 'lEN-ll-ili-B-QNES AND METHQD @F MAJKHNG 3A1Rudolf Wiech-crt, lilerlindliehterfeide, Emanuel Kaspar,BcriimWilmes'sdorf, and Martin Schenclr, Berlinhrohnuu, Germany,assignors to Schering A.G., Berlin, Germany, a corporation of Germany llo Drawing, Filed Aug. 13, lfifih, Ser. No. 334,3?8 Claims priority,application Germany Aug. 3t), 1958 8 Claims. (Cl. ass-397.4

This invention relates to novel anabolically active steroids and to themethod of their preparation. More particularly the invention isconcerned with Z-halogen derivatives of A and1'ostene-l7-ol-3-ones andtheir 17- esters.

The manufacture of preparations which in addition to strong anabolicactivity exhibit the least possible androgenie sidereactions, is ofgreat significance for therapeutic purposes. There are already knowncertain steroids closely related to testosterone, which in comparisonwith testosterone exhibit a slightly greater anabolic activity while atthe same time they possess notably lessened androgenic activity.Nevertheless, in the case of these steroids, the reduction of androgenicactivity is not so marked that they can no longer be used in dosagessuch as to evoke an extensive anabolic action. The discovery of newcompounds which shift the activity ratio in favor of anabolic activitytherefore undoubtedly represents a significant advance in the art.

it was now found that the introduction of a halogen atom into the2-position of the anabolically active A -an drostene-l7-,8-oi-3-one andits 17-esters unexpectedly and surprisingly brings about such a shift inthe activity ratio. Thus, for example, 2-chlor-A -androstene-1713-01-3-one in comparison with the unchlorinated compound, while possessingapproximately the same anabolic activity, shows a reduction inandrogenic activity to approximately one-fifth.

The therapeutic utility of the new halogenated com.- pounds has beenestablished by clinical tests, which are summarized in the followingTable I:

As seen from the data for compounds 1 and 2 in the table, the androgenicactivity of A -androstene-l7/3-o1-3- one is diminished about one'fifthby chlorination in the 2-position, While the anabolic activity remainsabout th same. A comparison of compounds 3 and 4 indicates that with17ot-niethyl-A -androstene-l7fi-ol-3-one the androgenic activity isdecreased to one-third by chlorination and the anabolic activity remainsthe same. Comparison of compounds 5 and 6 shows that a dosage of 12 w of2-chlor-A -l9-nor-androstene-17B-ol-3-one shows the same anabolicactivity as a dosage of 12X 10607 of 13 -19-nor-androstenc-l7fi-ol-3-one with a slightly smaller androgenicactivity. The relationship of compounds 7 and 8 is similar to that ofcompounds 5 and 6.

The hitherto undescribed Z-halogen-A -androstene-17- ol-3-one compoundscan be prepared in accordance with known methods of steroid chemistry. Apreferred starting material is l,2-oiridoandrostane-l7t3-ol-3-one. Ifthis substance is treated, for example, with hydrogen chloride inchloroform, there is immediately formed instead of the chlorhydrin whichmight have been expected, its dehydration product, 2-chlor-u-androstene-l7;3-ol-3--one, in accordance with the following sequence:

a it

Other suitable starting materials include the alcoholysis products ofl,2-oxido-androstane-l7-ol-one, particularly the methanolysis product,which is obtained, for example, from the foregoing oXido compound bytreatment with methanol in presence of perchloric acid. When thiscompound is treated with hydrogen chloride in chloroform there isimmediately formed, in an analogous manner, 2- chlor-u-androstene-17fi-ol-3-one in accordance with the following sequence:

OH I/\ 0 CH30;OH A

o: i o: A

The transformation using other hydrogen halides in place of hydrogenchloride takes place in analogous mans ner. Another method ofpreparation includes the halogenation of the unhalogenated u-androstenel7-ol-3-one compound with a solution of a halogen in analiphatic organic acid such as acetic acid or propionic acid. If de-'methylene chloride.

sired, the 17-hydroxy groups of the new 2-halogen-Aandrostene-17-ol3-ones can be acylated with any physiologicallytolerable acid. Examples of such acids include: acetic, formic,propionic, butyne, oenanthic, caprylic, undecylenic, undecylic,trimethylacetic, cyclopentylpropionic, hexahydrobenzoic, benzoic,phenylpropionic, methoxyphenylacetic, caprinoxylaeetic, tetrahydrofuranecarboxylic, chloracetic, 4-chlorphenoxyacetic, alanine, succinic,hexahydrophthalic, sulfuric, and phosphoric acids.

The invention is illustrated by the following examples, but it is not tobe considered as limited thereto:

Example 1 200 mg. of 1,2-oxido-androstane-175-01-3-one were dissolved in25 ml. of alcohol-free chloroform. Dry hydrogen chloride gas was passedinto this solution in the course of 2 hours and at a temperature of C.The solution was then diluted with water and extracted with methylenechloride. The methylene chloride phase was Washed with water untilneutral and dried over sodium sulfate. After evaporation of the solventthe residue was rubbed with ether, filtered by suction, andrecrystallized from ethyl acetate. 2-chlor A androstene-17fi-ol-3-onemelts at 221-222 C. The ultra-violet reading is 6243 9500.

Example 2 3.2 grams of 1,2-oxido-androstane-17,8-01-3-one were allowedto stand in 200 ml. methanol with 1.3 ml. of 70% perchloric acid at roomtemperature for 16 hours, and then worked up as described in Example 1.The residue thus obtained was rubbed with methanol, filtered by suctionand dried. The dry product (9.4% OCl-I ultraviolet inactive) melts at 7781 C. and is treated, as described in Example 1, with hydrogen chloridegas in chloroform, processed, and recrystallized. The yield is 2.9 gms.The recrystallized 2 chlor A androstene-17fl-ol-3-one melts at 221-222C. The ultraviolet reading is 6 9500. The mixed melting point with thecompound obtained in Example 1 showed no depression.

Example 3 50 mg. of 2-chlor-A -androstene-l75-ol-3-one, 0.2 ml. ofpyridine, and 0.1 ml. of acetic anhydride were heated on the steam bathfor 2 hours. This solution was then stirred into ice water. Theprecipitated 2-chlor-A androstene-17B-ol-3-one-l7-acetate was filteredby suction and recrystallized from isopropyl ether. It melts at 156 C.

Example 4 576 mg. of A -androstene-17 8-ol-3-one were dissolved in 8 cc.of chloroform, 0.8 cc. of acetic acid were added thereto and then underice cooling there was added dropwise with stirring over a period of 30minutes 335 mg. bromine in 9.4 cc. chloroform. After stirring foranother 30 minutes, the solution is diluted with methylene chloride,washed until neutral with water, the solution is dried over sodiumsulfate and evaporated to dryness in vacuo. The solid residue, treatedwith 5 cc. of dry pyridine, is allowed to stand overnight at roomtemperature with exclusion of moisture, the solution is then washed withwater and dried over sodium sulfate. After evaporating to dryness thesolid residue is recrystallized from ethyl acetate and there are thusobtained 470 mg. of 2-brom-A -androstene-17pol-3-one with a meltingpoint of 216218.5 C.; D 29.9 (c.=0.92; CHCl U.V. 6255:7450.

Example 5 1.15 g. of A -androstene-17p-ol-3-one were dissolved in 70 ml.tetrahydrofuran to which there was added at -60 C. 6.1 ml. propionicacid which contained 312 g. chlorine. Thi solution was stored in thedark at this temperature for 6 hours and then stirred into ice water.The aqueous solution was then extracted repeatedly with The methylenechloride phase was washed with sodium bicarbonate solution and finallywith water. After drying over sodium sulfate it is evaporated to drynessin vacuo and the residue is taken up with 6 ml. of pyridine. Afterstanding 19 hours it is diluted with ether, washed with 2 N HCl andfinally with water. After drying over sodium sulfate and evaporation ofthe ether solution the residue is recrystallized from ethyl acetate.There is obtained 800 mg. of 2-chlor-A -androstene-17/3- ol-3-one of m.pt. 221222 C. U.V. 5 :9500.

Example 6 639 mg. of l-methyl-A -androstene-17fi-ol-3-one is dissolvedin 38 ml. of tetrahydrofuran and cooled to -60 C. There is added to thissolution 165 mg. of chlorine in 1.9 ml. propionic acid. The temperatureis allowed to rise to -32 C. in the course of 6 hours and the solutionis then stirred into ice water. It is extracted with methylene chloride,and the methylene chloride phase is washed with sodium bicarbonatesolution and finally with water. After evaporation to dryness in vacuothe residue is stored overnight in 4 ml. pyridine at room temperature.It is then diluted with ether, and Washed with dilute hydrochloric acidand with water. After drying the ether phase over sodium sulfate it isevaporated to dryness in vacuo and the residue chromatographed oversilica gel. By elution with equal amounts of carbon tetrachloride andmethylene chloride, there is obtained Z-chlor-lmethyl-A-androstene-17fi-ol-3-one, which after recrystallization from isopropylether, melts at 156-157 C. U.V. 6203 2180, 257=1036O.

Example 7 302 mg. of 17a-methyl-A -androstene-17fi-ol-3-one in 15 ml. oftetrahydrofuran were treated with 78 mg. chlorine in 1 ml. of propionicacid, as described in Example 5, then further treated with 1.5 ml.pyridine and processed. The 2-chlor-17a-methyl-A-andr0stene-17fi-ol-3-one is recrystallized from isopropyl ether andmelts at 167168 C. U.V. 6247 9100.

Example 8 276 mg. of 19-n0r-A -androstene-17B-0l-3-one (m. pt. 146147C.; U.V. 6229 10650) Were dissolved in 10 ml. tetrahydrofuran andtreated with 78 mg. of chlorine in 1 ml. propionic acid, as described inExample 5; then further treated with 3 ml. pyridine and processed. Theproduct is recrystallized from isopropyl ether. The 2 chlor-19-nor-A-androstene-17/3 ol 3-one melts at 145- 146 C., U.V.e =9580.

Example 9 500 mg. 2-chlor-A -androstene-17p-ol-3-one were allowed tostand at room temperature for 50 hours in 2 ml. absolute pyridine and1.5 ml. propionic anhydride, and then stirred into ice water. Theprecipitation product was filtered by suction and recrystallized fromisopropyl ether. onate melts at 110-111" C. U.V.: 6240 230.

Example 10 2.5 g. 2chlor-A -androstene-17fi-ol-3-one were heated at 125.C. for minutes in 10 ml. absolute pyridine and 5 ml. oenanthicanhydride and then heated at C. for 60 minutes after adding thereto 0.2ml. of water. The residue remaining after steam distillation wasextracted with methylene chloride. The methylene chloride phase wasdried over sodium sulfate and evaporated to dryness in vacuum. 2-chlor-A-androstene-l7fi-ol-3-one- 17-oenanthate melts at 169171 C. whenrecrystallized from methanol. U.V.: 6 47 9300.

We claim:

1. An anabolically active steroid compound exhibiting low androgenicside reactions selected from the group consisting of 2-chlo-r-A-androstene-17fi-ol-3-one, 2-chlorl methyl A androstene-17B-ol-3-one,2-Cl1lOI-l7ocmethyl A androstene-17,8-ol-3-one, and the 17-estersthereof with physiologically tolerable acids selected from 2 chlor h-androstene-17/i-ol-3-one-17-propithe group consisting of inorganicacids and organic carboxylic acids.

2. Z-chlor-N-androstenei 7fl-o1-3-one.

3. 2-chlor-A -androstene-l7B-o1-3-one-17-acetate.

4. Z-chlor-1-methyl-A -androstene-17 51-01-3-one.

5. 2-ch1or-17a-methyl-A -androstene-17,8-01-3-one.

6. Process for the preparation of 2-chlor-A -andr0- stene-l7fl-o1-3-oneswhich comprises reacting 1,2oL-0Xid0- androstane-l7fi-ol-3-one with asolution of hydrogen chloride in chloroform.

7. Process for the preparation of 2-chlor-A -androstene-17 3-0l-3-oneswhich comprises treating 1,2a-oxidoandrostane-17,B-ol-3-one with amixture of methanol and perchloric acid and then reacting themethanolysis prodnot thus obtained with a solution of hydrogen chloridein chloroform.

8. Process for the preparation of 2-chlor-A -androstenel7flol-3-oneswhich comprises reacting A -androstene- 17B-ol-3-one with a solution ofchlorine in an aliphatic organic acid, and treating the resultingproduct with pyridine to form the 2-ch1or-A -steroid.

References Cited in the file of this patent Djerassi et 211.: Journal ofAmerican Chemical Society (1956), volume 78, page 6389.

1. AN ANABOLICALLY ACTIVE STEROID COMPOUND EXHIBITING LOW ANDROGENICSIDE REACTIONS SELECTED FROM THE GROUP CONSISTING OF2-CHLOR-$1-ANDROSTENE-17B-OL-3-ONE, 2-CHLOR1 - METHYL -$1 -ANDROSTENE-17B-OL-3-ONE, 2-CHLOR-17AMETHYL - $1 -ANDROSTENE-17B-OL-3-ONE, AND THE 17-ESTERS THEREOF WITH PHYSIOLOGICALLYTOLERABLE ACIDS SELECTED FROM THE GROUP CONSISTING OF INORGANIC ACIDSAND ORGANIC CARBOXYLIC ACIDS.